David L. Bigam

Gastric Adenocarcinoma: Review and Considerations for Future Directions

Objective:This update reviews the epidemiology and surgical management, and the controversies of gastric adenocarcinoma. We provide the relevance of outcome data to surgical decision-making and discuss the application of gene-expression analysis to clinical practice. Summary Background Data:Gastric cancer mortality rates have remained relatively unchanged over the past 30 years, and gastric cancer continues to be one of the leading causes of cancer-related death. Well-conducted studies have stimulated changes to surgical decision-making and technique. Microarray studies linked to predictive outcome models are poised to advance our understanding of the biologic behavior of gastric cancer and improve surgical management and outcome. Methods:We performed a review of the English gastric adenocarcinoma medical literature (1980–2003). This review included epidemiology, pathology and staging, surgical management, issues and controversies in management, prognostic variables, and the application of outcome models to gastric cancer. The results of DNA microarray analysis in various cancers and its predictive abilities in gastric cancer are considered. Results:Prognostic studies have provided valuable data to better the understanding of gastric cancer. These studies have contributed to improved surgical technique, more accurate pathologic characterization, and the identification of clinically useful prognostic markers. The application of microarray analysis linked to predictive models will provide a molecular understanding of the biology driving gastric cancer. Conclusions:Predictive models generate important information allowing a logical evolution in the surgical and pathologic understanding and therapy for gastric cancer. However, a greater understanding of the molecular changes associated with gastric cancer is needed to guide surgical and medical therapy.

Sirolimus‐based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma

Liver transplantation is an important treatment option for selected patients with nonresectable hepatocellular carcinoma (HCC). Several reports have suggested a lower risk of posttransplant tumor recurrence with the use of sirolimus and a higher one with calcineurin inhibitors, but the selection of an ideal immunosuppression protocol is still a matter of debate. The aim of this study was to define the immunosuppression associated with the best survival after liver transplantation for HCC. It was based on the Scientific Registry of Transplant Recipients and included 2,491 adult recipients of isolated liver transplantation for HCC and 12,167 for non‐HCC diagnoses between March 2002 and March 2009. All patients remained on stable maintenance immunosuppression protocols for at least 6 months posttransplant. In a multivariate analysis, only anti‐CD25 antibody induction and sirolimus‐based maintenance therapy were associated with improved survivals after transplantation for HCC (hazard ratio [HR] 0.64, 95% confidence interval [CI]: 0.45–0.9, P ≤ 0.01; HR 0.53, 95% CI: 0.31–0.92, P ≤ 0.05, respectively). The other studied drugs, including calcineurin inhibitors, did not demonstrate a significant impact. In an effort to understand whether the observed effects were due to a direct impact of the drug on tumor or more on liver transplant in general, we conducted a similar analysis on non‐HCC patients. Although anti‐CD25 induction was again associated with a trend toward improved survival, sirolimus showed a trend toward lower rates of survival in non‐HCC recipients, confirming the specificity of its beneficial impact to cancer patients. Conclusion: According to these data, sirolimus‐based immunosuppression has unique posttransplant effects on HCC patients that lead to improved survival. (HEPATOLOGY 2010.)

Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the scientific registry of transplant recipients database

The current model of liver graft allocation in place in the United States favors transplantation of patients with small hepatocellular carcinomas (HCCs) within the Milan criteria (a single tumor up to 5 cm in diameter or up to three lesions, none larger than 3 cm). Although several reports have suggested that these criteria could be extended, there is currently no agreement on new selection tools. In this study, we performed an overview of 6478 adult recipients of an isolated first liver transplant registered in the Scientific Registry of Transplant Recipients (SRTR) database. From March 2002 to January 2008, increasing numbers of patients outside Milan criteria (P ≤ 0.001) have been registered for a transplant, but they still represent less than 5% of the transplants performed for HCC. Of all the tested variables (tumor number, largest tumor size, and Milan and University of California San Francisco criteria), only total tumor volume (TTV; P ≤ 0.05) and alpha fetoprotein (AFP; P ≤ 0.001) could predict patient survival. While these two parameters demonstrated independent behaviors (no patient demonstrated an increase in both values), a composite score was defined, with patients with a TTV > 115 cm3 or an AFP > 400 ng/mL being outside criteria. The combined TTV/AFP score efficiently predicted posttransplant survival (hazard ratio = 2, 95% confidence interval = 1.7‐2.4, P ≤ 0.001); patients not meeting these criteria had a survival below 50% at 3 years. Conclusion: According to the present SRTR data, Milan criteria are too restrictive, and patients with larger TTV can enjoy satisfactory posttransplant survivals. A composite patient selection score combining TTV and AFP was the most effective of all tested staging criteria for the prediction of posttransplant patient survival for candidates with HCC. (HEPATOLOGY 2009.)

Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma.

An increasing number of patients with hepatocellular carcinoma (HCC) are undergoing evaluation for listing for liver transplantation. Criteria for selection require ongoing review for suitability. A consecutive series of 40 patients with HCC within the standard Milan criteria (single tumors n = 19 <5 cm, or up to 3 tumors <3 cm) and beyond (Extended Criteria; single tumors n = 21 <7.5 cm, multiple tumors <5 cm) underwent liver transplant with a sirolimus‐based immunosuppressive protocol designed to minimize exposure to calcineurin inhibitors and steroids. At 44.3 ± 19.3 months (mean ± standard deviation) follow‐up, 1‐ and 4‐year survivals (Kaplan‐Meier) are 94.1 ± 5.7% and 87.4 ± 9.3%, in the Milan group, respectively, and 90.5 ± 6.4% and 82.9 ± 9.3% in the Extended Criteria group, respectively. Five patients died during follow‐up, only 1 from recurrent HCC. Five tumor recurrences have occurred at median 17 (mean 22 ± 17) months posttransplant, 1 in the Milan group and 4 in the Extended Criteria group. Median survival in the patients with recurrent tumor is 42 months (mean 45 ± 25), and the median postrecurrence survival is 15.5 months (mean 23 ± 16). The rate of patients who were alive and free of tumor at 1 and 4 years is 94.1 ± 5.7% and 81.1 ± 9.9%, respectively, in the Milan group and is 90.5 ± 6.4% and 76.8 ± 10.5%, respectively, in the Extended Criteria group. Five patients had sirolimus discontinued for toxicity, while 24 of 35 surviving patients have sirolimus monotherapy immunosuppression. In conclusion, the Milan criteria for liver transplantation in the presence of HCC can be carefully extended without compromising outcomes. This sirolimus based immunosuppression protocol appears to have beneficial effects on tumor recurrence and survival with an acceptable rate of rejection and toxicity. (Liver Transpl 2004;10:1301–1311.)

De novo sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: Long-term outcomes and side effects

Background. We report long-term outcomes and side effects after transplantation for hepatocellular carcinoma (HCC) using de novo, sirolimus-based immunosuppression (IS). Methods. A total of 70 patients with HCC (mean age: 54.4±7 years, female/male: 12/58) were transplanted and included in the study. Immunosuppression included de novo sirolimus, low-dose calcineurin inhibitor for 6 to 12 months, with short-course (3 months) or no steroids. Results. After 49 months-median follow-up, eight patients have experienced an HCC recurrence, 2 of 34 when Milan criteria were respected (6%) and 6 of 36 when beyond Milan criteria (17%). One- and 4-year tumor-free survivals were 85 and 73%, when Milan criteria were respected and 82% and 75% when they were not, respectively. (P=0.9). After recurrence, mean survival was 23±28 months. Half (35 of 70) of the patients experienced a rejection. Incisional hernia (24 of 70, 34%), wound infection (12 of 70, 17%), anemia (39 of 70, 56%), leucopenia (39 of 70, 56%), high triglyceride (43 of 70, 61%), and cholesterol (28 of 70, 40%) levels and mouth ulcers (20 of 70, 29%) were among the most frequent complications. No hepatic artery thrombosis was observed. Conclusions. These data suggest that de novo sirolimus-based immunosuppression is associated with satisfactory outcomes after transplantation, even in selected patients beyond Milan criteria. The protocol has proven safe, with an acceptable side-effect profile. This study supports the conduct of larger randomized trials investigating sirolimus after transplantation for HCC.

High risk of sensitization after failed islet transplantation.

Human Leukocyte Antigen (HLA) antibodies posttransplant have been associated with an increased risk of early graft failure in kidney transplants. Whether this also applies to islet transplantation is not clear. To achieve insulin independence after islet transplants multiple donor infusions may be required. Hence, islet transplant recipients are at risk of sensitization after transplantation. Islet transplant recipients were screened for HLA antibodies posttransplant by flow‐based methods. A total of 98 patients were studied. Twenty‐nine patients (31%) developed de novo donor specific antibodies (DSA) posttransplant. Twenty‐three patients developed DSA while on immunosuppression (IS). Among recipients who have discontinued IS, 10/14 (71%) are broadly sensitized with panel reactive antibody (PRA) ≥50%. The risk of becoming broadly sensitized after transplant was 11/69 (16%) if the recipient was unsensitized prior to transplant. The majority of these antibodies have persisted over time. Appearance of HLA antibodies posttransplant is concerning, and the incidence rises abruptly in subjects weaned completely from IS. This may negatively impact the ability of these individuals to undergo further islet, pancreas or kidney transplantation and should be discussed upfront during evaluation of candidates for islet transplantation.

Total tumor volume predicts risk of recurrence following liver transplantation in patients with hepatocellular carcinoma

Criteria for the selection of candidates for liver transplantation in the presence of hepatocellular carcinoma (HCC) should accurately predict posttransplant recurrence while not excluding excessive numbers of patients from candidacy. Existing criteria are challenged by the limited accuracy of radiological assessment. The total tumor volume (TTV) was calculated by the addition of the volume of each individual tumor. A preliminary analysis was carried out on HCC patient data from the Alberta Liver Transplant Program (52 patients) and then validated on the populations of the Universities of Toronto and Colorado programs (154 and 82 patients). A TTV cutoff of 115 cm3 was chosen on the basis of the risk of recurrence with use of a receiver operating characteristic curve. Radiology correlated more closely to pathology with TTV than with Milan and University of California at San Francisco (UCSF) criteria (91% versus 69% and 75% of patients, P < 0.0001). Although more patients met qualifying criteria for transplant with TTV (28%‐53% more than Milan and 16%‐26% more than UCSF), no deterioration of outcome was demonstrated in an analysis of patients within TTV ≤ 115 cm3 in comparison with those meeting Milan or UCSF classifications at all institutions. Patients with TTV > 115 cm3 experienced more recurrences and lower patient survival in the Alberta and Colorado series (P < 0.05). When TTV with a cutoff of 115 cm3 is used for candidate selection, the accuracy of pretransplant radiological assessment is enhanced, with posttransplant outcomes not different from those achieved with Milan and UCSF classifications despite a more inclusive patient population. Liver Transpl 14:1107–1115, 2008.

Portal venous pressure changes after sequential clinical islet transplantation.

Background. Sequential pancreatic islet transplantation via the portal vein has led to insulin independence in patients with type 1 diabetes. Complications associated with the injection of islets into the portal vein have been reported; therefore, in this study we sought to further characterize changes in portal venous pressure associated with islet infusion. Methods. Pre- and posttransplant portal venous pressures were recorded in 50 consecutive transplant procedures in 26 patients receiving highly purified, heparinized allogeneic islet preparations via a radiologically placed portal venous cannula. Doppler ultrasound scans of the portal vein were completed within 24 hr of transplantation. Results. Posttransplant portal vein pressures rose significantly with sequential transplantation (12.4 mm Hg vs. 17.3 mm Hg, P <0.05). Portal pressure change correlated significantly with islet packed cell volume (r =0.66, P <0.001) and also with the number of islets transplanted (r =0.49, P <0.001). Segmental portal vein thrombosis was radiologically detected after two procedures (4%). Conclusion. Multiple sequential islet transplants can be safely performed via the portal vein, provided that care is taken with islet purification and attention is paid to portal venous monitoring.

Prevention of Bleeding After Islet Transplantation: Lessons Learned from a Multivariate Analysis of 132 Cases at a Single Institution

Islet transplantation is being offered increasingly for selected patients with unstable type 1 diabetes. Percutaneous transhepatic portal access avoids a need for surgery, but is associated with potential risk of bleeding. Between 1999 and 2005, we performed 132 percutaneous transhepatic islet transplants in 67 patients. We encountered bleeding in 18/132 cases (13.6%). In univariate analysis, the risk of bleeding in the absence of effective track ablation was associated with an increasing number of procedures (2nd and 3rd procedures with an odds ratio (OR) of 9.5 and 20.9, respectively), platelets count <150 000 (OR 4.4), elevated portal pressure (OR 1.1 per mm Hg rise), heparin dose ≥45 U/kg (OR 9.8) and pre‐transplant aspirin (81 mg per day) (OR 2.6, p = 0.05). A multivariate analysis further confirmed the cumulative transplant procedure number (p < 0.001) and heparin dose ≥45 U/kg (p = 0.02) as independent risk factors for bleeding. Effective mechanical sealing of the intrahepatic portal catheter tract with thrombostatic coils and tissue fibrin glue completely prevented bleeding in all subsequent procedures (n = 26, p = 0.02). We conclude that bleeding after percutaneous islet implantation is an avoidable complication provided the intraparenchymal liver tract is sealed effectively.

Pretransplant HLA antibodies are associated with reduced graft survival after clinical islet transplantation.

Despite significant improvements in islet transplantation, long‐term graft function is still not optimal. It is likely that both immune and nonimmune factors are involved in the deterioration of islet function over time. Historically, the pretransplant T‐cell crossmatch and antibody screening were done by anti‐human globulin—complement‐dependent cytotoxicity (AHG‐CDC). Class II antibodies were not evaluated. In 2003, we introduced solid‐phase antibody screening using flow‐based beads and flow crossmatching. We were interested to know whether pretransplant human leukocyte antigen (HLA) antibodies or a positive flow crossmatch impacted islet function post‐transplant. A total of 152 islet transplants was performed in 81 patients. Islet function was determined by a positive C‐peptide. Results were analyzed by procedure. Class I and class II panel reactive antibody (PRA) > 15% and donor‐specific antibodies (DSA) were associated with a reduced C‐peptide survival (p < 0.0001 and p < 0.0001, respectively). A positive T‐ and or B‐cell crossmatch alone was not. Pretransplant HLA antibodies detectable by flow beads are associated with reduced graft survival. This suggests that the sirolimus and low‐dose tacrolimus‐based immunosuppression may not control the alloimmune response in this presensitized population and individuals with a PRA > 15% may require more aggressive inductive and maintenance immunosuppression, or represent a group that may not benefit from islet transplantation.